Periodontal diseases are infectious diseases, but the specific mechanism by which the tooth-supportive tissue is destroyed is not clearly understood. Viral infection impairs periodontal defenses, thereby permitting subgingival overgrowth of periodontopathic bacteria. The role of viruses is significant, as they may induce abnormalities in the adhesion, chemotaxis, phagocytosis, and bactericidal activities of polymorphonuclear leukocytes. When associated with one another, viruses and bacteria have stronger periodontopathogenic potential than individually. Therefore, it is significant to know all etiologic factors and such an insight would lead to the better treatment of the disease.

Periodontitis is a multifactorial, chronic disease followed by destruction of encompassing structures of teeth and when left untreated leads to loss of alveolar bone and exfoliation of the involved teeth. The main etiological factor for development of periodontitis is oral biofilm containing anaerobic microorganisms. Microbiological culture studies have identified more than 1200 bacterial species in the oral cavity [1]. Although the role of bacterial plaque in general seems to be evident, on the contrary the role of virus have been largely unexplored and remains unclear.

Etiopathogenesis

Many bacterial infections in humans occur as superinfections of viral diseases [2]. A study found a significantly higher prevalence of human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) in subgingival specimens from adult periodontitis patients as compared to periodontally healthy or gingivitis patients [3]. Viruses may participate in the pathogenesis of human periodontitis by altering immunological defenses, by activating destructive host reactions or by producing direct lytic effects on periodontal tissues [4],[5]. For viral infection to occur in body following steps are required that is entry, replication, dissemination and infection of target cells/organs [Figure 1]. Latent viruses persisting in body can become reactivated by several immune compromising events, such as smoking, inflammation, stress, trauma, and immunosuppressive diseases [6].

Herpesviruses came into the sight of periodontists as putative pathogens of periodontal disease in the mid-1990s. Herpesviruses are the most common viruses in humans, infecting 80–90% of the global adult population [7]. Eight members of the herpes family are known to cause human disease. These are EBV, HCMV, herpes simplex virus 1 and 2 (HSV-1, HSV-2), varicella zoster virus, human herpesvirus (HHV) 6, HHV-7, and HHV-8. To survive, herpesviruses need to exploit macrophages, lymphocytes, or other host cells for replication, while minimizing antiviral inflammatory responses of the host. Herpesvirus may cause periodontal disease as a direct result of virus infection and replication, or as a consequence of virally induced impairment of periodontal host defences with heightened aggressiveness of resident bacterial pathogens.

Therefore, the hallmark of herpes infection is immune impairment. Herpesvirus-associated periodontal sites also tend to harbor elevated levels of periodontopathic bacteria, including Porphyromonas gingivalis, Tannerella forsythia, Dialister pneumosintes/Dialister invisus, Prevotella intermedia, Prevotella nigrescens, Treponema denticola, Campylobacter rectus, and Aggregatibacter actinomycetemcomitans. The coexistence of periodontal HCMV, EBV, and possibly other viruses, periodontopathic bacteria, and local host immune responses should be viewed as a precarious balance that has the potential to lead to periodontal destruction [8][Figure 2]. Initially, bacterial infection of the gingival causes inflammatory cells to enter gingival tissue, with periodontal macrophages and T-lymphocytes harboring latent HCMV and periodontal B-lymphocytes harboring latent EBV. Immunoglobulin A antibodies against HCMV, EBV, and HSV in gingival crevice fluid seem to originate mainly from local plasma cell synthesis rather than from passive transudation from serum, which is a further indication of a gingival herpesvirus presence [9],[10].

Herpes viral activation leads to increased inflammatory mediator responses in macrophages and probably also in connective tissue cells within the periodontal lesion. After reaching a critical virus load, activated macrophages and lymphocytes may trigger a cytokine/chemokine 'storm' of interleukin (IL)-1β, TNF-α, IL-6, prostaglandins, interferons, and other multifunctional mediators, some of which have the potential to propagate bone resorption [11]. In a vicious circle, the triggering of cytokine responses may activate latent herpesviruses, and that may further aggravate periodontal disease. It is conceivable that herpesviruses rely on coinfection with periodontal bacteria to produce periodontitis and, conversely, periodontopathic bacteria may depend on viral presence for the initiation and progression of some types of periodontitis [12]. A recently conducted meta-analysis provided circumstantial evidence that herpesviruses play a role in chronic periodontitis; nevertheless, a cause-and-effect relationship remains to be established. The possible involvement of HHVs in the pathogenesis of chronic periodontitis merits further investigation [13].

Epstein–Barr virus and periodontitis

EBV affects over 90% of humans, and is usually transmitted by oral secretions or blood. The virus replicates in epithelial cells or B cells of oropharynx. Almost all of seropositive persons have an active virus in the saliva. Memory B cells are the main site of persistence of EBV [14],[15]. In periodontitis, the presence of EBV DNA is related to an elevated occurrence of Porphyromonas gingivalis, Tannerella forsythia, Campylobacter spp. and other periodontopathic bacteria. Bacterially induced gingivitis permits EBV-infected B lymphocytes to enter the periodontium. These cells are prominent in progressive periodontal lesions. Oral hairy leukoplakia is the main lesion associated to EBV. Clinically oral hairy leukoplakia appears as a raised, white, corrugated lesion that most often develops on the ventral–lateral aspect of the tongue.

Human cytomegalovirus and periodontitis

HCMV is the most common cause of congenital and perinatal infections. HCMV infects many different epithelial cells, endothelial cells, smooth muscle cells, mesenchymal cells, hepatocytes, granulocytes, and monocyte-derived macrophages. It is thus found in many body secretions including saliva, urine, semen, and breast milk. HCMV infection, although generally subclinical, is responsible for cytomegalovirus inclusion disease and mononucleosis [16]. In response to the bacterial challenge the gingival connective tissue reacts by recruiting monocytes, macrophages and neutrophils, followed by CD4 cells in a T-helper 1 and T-helper 2 combined response. The cytomegalovirus latent genome is carried into the periodontium by infected macrophages and T cells, and cytomegalovirus activation may eventually give rise to infection of additional cell types. The down regulation of these cells involved in the periodontal defense may lead to bacterial superinfection resulting in increased virulence of resident bacteria including Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens, Campylobacter rectus, Treponema denticolaand Aggregatibacteractinomycetemcomitans.

An active cytomegalovirus infection in macrophages and T cells triggers release of IL-1β and tumor necrosis factor (TNF) α. These proinflammatory mediators recruit antiviral inflammatory cells to the site of infection but also induce osteoclast differentiation and the release of matrix metalloproteinases (MMPs) [Figure 3]. An active cytomegalovirus periodontal infection has been associated to disease-active periodontitis, and the virus may play a role in other types of periodontal disease such as aggressive and refractory periodontitis [17].

Oral lesions associated to HIV are often the first clinical signs of this infection and can play a specific role in the diagnosis of patients with unknown HIV serostatus. The European Community Clearing house on oral problems related to HIV Infection and WHO Collaborating Centre on oral manifestations of the HIV classified periodontal diseases as lesions strongly associated with HIV infection [18]. The frequent routes of transmission of HIV are sexual contact, parenteral exposure to blood or mother to child transmission. The primary target of HIV is CD4+-helper T cells. HIV becomes incorporated into the DNA of the lymphocyte and become present for the life of the cell. It may remain latent for a period but soon becomes active and cause cell death. A decrease in the number of T-helper cell number occurs with a resultant loss in immune function. It is this reduction in immune function that predisposes the individual to a number of opportunistic infection including periodontal diseases and also facilitate herpesviruses' reactivation or reinfection [19]. Oral lesions which are strongly associated with HIV-infected patients are non-Hodgkin's lymphoma, oral candidiasis and Kaposi's sarcoma. In addition to this, four forms of HIV-associated periodontal disease have been described: linear gingival erythema, necrotizing ulcerativegingivitis, necrotizing ulcerative periodontitis, and necrotizing stomatitis. If left untreated, HIV-associated periodontal disease may progress to life-threatening infections, such as Ludwig's angina and cancrum oris. A study compared MMPs in gingival crevicular fluid (GCF) and saliva from HIV +-patients HIV +-patients with adult periodontitis and controls. Results determined that POLYMORPHONUCLEAR-derived metalloproteinases in GCF and saliva from HIV +-patients were present in the activated form, and proposed that these activated enzymes may contribute to periodontal destruction in HIV +-patients [20].

Inversely, periodontal disease may also be involved in the onset of AIDS-related pathological changes in oral hairy leukoplakia and Kaposi's sarcoma. In individuals with AIDS, HIV-infected lymphocytes and monocytes are abundant at oral sites, including periodontal pockets, gingival tissues, and salivary glands. Direct interaction of these cells with periodontopathic bacteria and/or indirect interaction with soluble factors (e.g. butyric acid and TNF-α) could induce local HIV-1 replication in the oral cavity. It is possible that a cell in which viral transcription has been reactivated by a stimulus spread throughout the body via the blood. In addition, TNF-α concentrations are known to be elevated in individuals with periodontal disease, which suggests that periodontal disease is a trigger for local and systemic breakdown of latent infection and may be a risk factor for AIDS progression [21].

Human papillomavirus and periodontitis

HPV belongs to Papillomaviridae family and is a double stranded, nonenveloped DNA virus. HPV has tropism for epithelial tissue thus; it can affect both skin and mucosa. HPV causes characteristic cytopathic effects (koilocytosis) and proliferation of epithelial cells. Since proliferation and migration of the junctional epithelium are a major hallmark of periodontal breakdown, these known biological effects of HPV might provide a link between viral infection and periodontal disease [22],[23][Figure 4]. A study confirmed that HPV types 6, 11, and 16 DNA are detected in gingival samples from patients with periodontal disease explaining the development of gingival papillomas and condylomas in the oral cavity [24].

Viral diagnosis is a challenging task in periodontal cases; however the revolution in the field of diagnostic made it easy now a day. Gold-standard method of virus culture is in vitro and in vivo but is a time consuming process. Rapid diagnosis can be achieved by molecular techniques like PCR, reverse transcription-PCR. Other successful diagnostic approach is use of DNA microarrays, it uses multiplex real-time PCR techniques to quantify the number of genome-copies simultaneously. The presence of viral species through DNA probes, flow cytometry, immunofluorescence staining, and culture [25].

Discussion

Researches of the virus impact on periodontitis are intended to lead to better understanding and clarification of etiopathogenesis of this disease. Parra and Slots [3] in their study concluded that gingival infection with certain herpesviruses lowers the resistance of the periodontal tissues, thereby permitting subgingival overgrowth of anaerobic and other periodontal pathogenic bacteria. Banks and Rouse [5] postulated that EBV and HCMV can infect monocytes, macrophages and lymphocytes and can also alter their functions. These infected inflammatory cells stimulate tissue destructive cytokines and decrease the defensibility against periodontal bacteria [6]. Saygun et al.[8] detected subgingival HCMV and EBV-1 in 72% of aggressive periodontitis lesions. Based on the observations by Salo et al.[20] activated forms of PMN-derived MMPs (collagenase-2 and gelatinase B) and high levels of their inhibitors have been found in GCF and saliva of HIV +-patients with aggressive periodontitis. All the above findings contribute to periodontal pathogenesis. Therefore, transient immunosuppressive effect of viral reactivation in periodontal tissues might explain in part the episodic progressive nature of human periodontitis.

Better understanding of etiology of periodontitis is critical for developing detection systems and therapies that will enable periodontists to ensure disease control. Maintaining gingival health by professional periodontal therapy and oral hygiene measures reduce the risk of transmissible viral disease. Rapid advances in medical virology may also help to uncover the pathogenesis and treatments of viral diseases of mouth. Prevention and therapy based upon antiviral approaches might avert the initiation, progression of periodontal disease caused by viruses.